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12.20.2011

Researcher’s Dual Studies Link Pediatric HIV Therapy to Premature Cardiovascular Disease

Tracie L. Miller, M.D., professor of pediatrics and director of the Division of Pediatric Clinical Research, published two major multicenter studies this month that found HIV-positive children exposed to antiretroviral drugs in utero or at birth are at higher risk for developing premature cardiovascular disease.

Both studies were conducted under the auspices of the NIH-funded Pediatric HIV/AIDS Cohort Study (PHACS) network, which was established to evaluate the long-term consequences of antiretroviral therapies administered early in life. Miller’s studies, one of which appeared in HIV Medicine, the official journal of The British HIV Association, and the other in The American Journal of Clinical Nutrition, collectively suggest that clinicians should carefully monitor HIV-infected children for abnormal vascular markers of premature atherosclerosis, abnormal lipid measurements, and abnormal body composition to identify those at highest risk for cardiovascular and cardiometabolic disease so appropriate interventions are initiated.

“It appears that remarkable improvements in survival brought on by antiretroviral therapies may come at the expense of premature cardiovascular disease,’’ said Miller, who was first author on the HIV Medicine study, and senior author on The American Journal of Clinical Nutrition study. “Cardiovascular disease is now a leading cause of mortality in adults with HIV, and it appears that children with HIV are destined for the same fate unless clinicians intervene early.’’

The HIV Medicine study, “Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children,” was published online December 4 and in the December print edition.

Researchers on this study compared the levels of vascular dysfunction, including inflammation, and coagulant, endothelial and metabolic dysfunction, in 366 children enrolled in the PHACS network, 226 of whom were HIV-infected at birth and 140 whose mothers were HIV-positive but were born uninfected. They found that the HIV-infected children, with a median age of 12.3 years, had higher levels of biomarkers of vascular dysfunction, including unfavorable lipid levels and active HIV replication, than did the exposed but uninfected children, whose median age was 10.1 years.

“In this current era of HIV treatment, children who have been infected with HIV for more than 10 years have clear evidence of vascular dysfunction,’’ said Miller, who is a member of the PHACS Scientific Leadership Group and leader of its working group on Growth, Nutrition, and Metabolism. “They have higher levels of biomarkers that can be associated with premature atherosclerosis when compared to a sociodemographically similar group of children who are not infected.’’

Noting that active HIV replication and unfavorable lipid profiles were more common with higher vascular inflammatory biomarkers, Miller said the study suggests that modifiable risk factors be targeted for therapeutic interventions to reduce cardiovascular risk.

Miller collaborated with a dozen co-authors on the HIV Medicine study, including the Miller School’s Armando J. Mendez, Ph.D., research assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism and member of the Diabetes Research Institute, and researchers from eight other institutions, including the Harvard School of Public Health, the Keck School of Medicine of the University of Southern California, and NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The study in The American Journal of Clinical Nutrition, “Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study,” debuted online on November 2 and appears in the journal’s December print edition.

For this study, researchers set out to better understand the association between abnormal body fat distribution and clinical variables in pediatric HIV disease and compared the total body fat and its distribution in 545 children born to HIV-infected mothers. Nearly 370 children, ranging in age from 7 to 16, were HIV-infected and 176 were not.

The researchers found that, while the body mass index and total body fat of children in the HIV-infected group were significantly lower than the non-infected children, the former group had greater fat in their abdomen and less in their extremities, a fat distribution pattern associated with cardiovascular disease risk and possibly related to specific antiretroviral drugs, such as stavudine.

“This is in spite of the fact that these HIV-infected children were of normal weight,’’ Miller said “For the HIV-uninfected children born to HIV-infected women, there were high rates of obesity.”

Miller was joined by 12 collaborating co-authors from ten institutions on this study, with Harvard, Keck and the NICHD again among them.

Established in 2005, PHACS is the largest study of pediatric HIV in the U.S. and has enabled researchers to systematically study the long-term safety of fetal and infant exposure to prophylactic antiretroviral chemotherapy, and the effects of perinatally acquired HIV infection on the growth and development of adolescents.

As Steven E. Lipshultz, M.D., professor and chairman of pediatrics and associate executive dean for child health at the Miller School, noted, these are critical research queries, especially given that more than half of the approximately 15 million HIV-infected women of childbearing age in the world receive antiretroviral therapy when they become pregnant.

“While antiretroviral therapy saves the lives of thousands of children born to HIV-positive mothers, it’s long been suspected that these strong medications come with long-term safety concerns,’’ said Lipshultz, a member of the PHACS Scientific Leadership Group who helped write the initial grant that established the PHACS, which to date has received more than $100 million in NIH funding. “We hope that by closely analyzing health indicators among HIV-positive and antiretroviral therapy-exposed children, we can suggest to clinicians how to adjust therapy or step in with remedial interventions to minimize any aftereffects of live-saving treatment.”

Other UM faculty are actively involved with the PHACS network, and contributed to the Miller studies. Gwendolyn Scott, M.D., professor of pediatrics, director of Pediatric Infectious Diseases and Immunology, principal investigator of the University of Miami PHACS Clinical Center and leader of the principal investigators group for PHACS, participated in both articles. James D. Wilkinson, M.D., M.P.H., professor of pediatrics and epidemiology and public health, and senior epidemiologist in the Division of Pediatric Clinical Research, leads several PHACS writing committees on cardiovascular complications.

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